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Risk factors for COVID-19 hospitalization after COVID-19 vaccination: a population-based cohort study in Canada

Open AccessPublished:December 07, 2022DOI:https://doi.org/10.1016/j.ijid.2022.12.001

      Highlights

      • The risk factors for COVID-19-related hospitalization differ by vaccination status.
      • The overall risk is more reduced among vaccinated individuals.
      • Seniors and those with underlying medical conditions may benefit from booster doses.

      Abstract

      Objectives

      With the uptake of COVID-19 vaccines, there is a need for population-based studies to assess risk factors for COVID-19-related hospitalization after vaccination and how they differ from unvaccinated individuals.

      Methods

      We used data from the British Columbia COVID-19 Cohort, a population-based cohort that includes all individuals (aged ≥18 years) who tested positive for SARS-CoV-2 by real-time reverse transcription-polymerase chain reaction from January 1, 2021 (after the start of vaccination program) to December 31, 2021. We used multivariable logistic regression models to assess COVID-19-related hospitalization risk by vaccination status and age group among confirmed COVID-19 cases.

      Results

      Of the 162,509 COVID-19 cases included in the analysis, 8,546 (5.3%) required hospitalization. Among vaccinated individuals, an increased odds of hospitalization with increasing age was observed for older age groups, namely those aged 50-59 years (odds ratio [OR] = 2.95, 95% confidence interval [CI]: 2.01-4.33), 60-69 years (OR = 4.82, 95% CI: 3.29, 7.07), 70-79 years (OR = 11.92, 95% CI: 8.02, 17.71), and ≥80 years (OR = 24.25, 95% CI: 16.02, 36.71). However, among unvaccinated individuals, there was a graded increase in odds of hospitalization with increasing age, starting at age group 30-39 years (OR = 2.14, 95% CI: 1.90, 2.41) to ≥80 years (OR = 41.95, 95% CI: 35.43, 49.67). Also, comparing all the age groups to the youngest, the observed magnitude of association was much higher among unvaccinated individuals than vaccinated ones.

      Conclusion

      Alongside a number of comorbidities, our findings showed a strong association between age and COVID-19-related hospitalization, regardless of vaccination status. However, age-related hospitalization risk was reduced two-fold by vaccination, highlighting the need for vaccination in reducing the risk of severe disease and subsequent COVID-19-related hospitalization across all population groups.

      Keywords

      1. Introduction

      As of July 24, 2022, over 560 million confirmed cases of COVID-19 have been reported worldwide, with over 6 million deaths. Almost four million confirmed cases, including 42,215 deaths, have been reported in Canada alone [

      Johns Hopkins University. COVID-19 Map, https://coronavirus.jhu.edu/map.html; 2022 [accessed 24 July 2022].

      ]. In British Columbia (BC), Canada's third largest province by population size, over 370, 000 cases have been recorded, with over 3,855 deaths as of July 24, 2022 [

      British Columbia Centre for Disease Control. British Columbia COVID-19 Dashboard, https://experience.arcgis.com/experience/a6f23959a8b14bfa989e3cda29297ded; 2022a [accessed 24 July 2022].

      ]. Although vaccination roll-out and uptake have reduced COVID-19 disease burden in many jurisdictions, prompting the opening of economies and a return to normalcy, the effects of COVID-19 are far from over.
      Hospitalization is commonly used as a measure of COVID-19 severity. Since the beginning of the pandemic, there has been an emergence of a growing number of studies assessing the risk factors of COVID-19 hospitalization. These studies have established certain key risk factors; prominent among them are age, sex, and certain comorbidities. However, most of these studies were hospital-based [
      • Gold JAW
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      • Burton DC
      • Uyeki TM
      • Bialek SR
      • Jackson BR
      Characteristics and clinical outcomes of adult patients hospitalized with COVID-19 — Georgia, March 2020.
      ,
      • Kaeuffer C
      • Le Hyaric C
      • Fabacher T
      • Mootien J
      • Dervieux B
      • Ruch Y
      • et al.
      Clinical characteristics and risk factors associated with severe COVID-19: prospective analysis of 1,045 hospitalised cases in North-Eastern France, March 2020.
      ,
      • Vahey GM
      • McDonald E
      • Marshall K
      • Martin SW
      • Chun H
      • Herlihy R
      • et al.
      Risk factors for hospitalization among persons with COVID-19-Colorado.
      ], with few population-based studies involving all diagnosed patients in a jurisdiction. Vaccination has resulted in the prevention of severe disease that would lead to hospitalization, intensive care unit (ICU) admission, and mortality [
      • Nasreen S
      • Febriani Y
      • Velásquez García HA
      • Zhang G
      • Tadrous M
      • Buchan SA
      • et al.
      Effectiveness of COVID-19 vaccines against hospitalization and death in Canada: a multiprovincial, test-negative design study.
      ,
      • Watson OJ
      • Barnsley G
      • Toor J
      • Hogan AB
      • Winskill P
      • Ghani AC.
      Global impact of the first year of COVID-19 vaccination: a mathematical modelling study.
      ]. However, it was not very well established during the time of high vaccine effectiveness, which population groups remained at the risk of hospitalization, and whether these risk factors and the magnitude of association differed by vaccination status. These data could identify candidates for additional interventions, such as pharmacotherapy, to reduce the risk of hospitalization and severe disease. In addition, this evidence will help improve health outcomes and maintain health system capacity. Therefore, the aim of this study was to assess COVID-19-related hospitalization risk by vaccine status and age among confirmed COVID-19 cases during the period of high vaccine effectiveness.

      2. Materials and methods

      2.1 Study design and data sources

      We used data from the BC COVID-19 Cohort (BCC19C; https://a4ph.med.ubc.ca/projects-and-initiatives/bc-covid-19-cohort/]), a population-based data platform that has been established as a public health surveillance system under the BC Centre for Disease Control's public health mandate [
      • Velásquez García HA
      • Wilton J
      • Smolina K
      • Chong M
      • Rasali D
      • Otterstatter M
      • et al.
      Mental health and substance use associated with hospitalization among people with COVID-19: a population-based cohort study.
      ]. The BCC19C integrates data on all individuals tested for COVID-19 in BC, with data on COVID-19 hospital and ICU admissions, medical visits, hospitalizations, emergency room visits, chronic conditions, prescription drugs, and mortality (see Appendix A of the Supplementary file).

      2.2 Study population

      This analysis included all adult individuals (aged 18 or older) who tested positive for SARS-CoV-2 by real-time reverse transcription-polymerase chain reaction from January 01, 2021 to December 31, 2021. During this period, vaccination coverage (at least two doses) for all eligible ages ranged from 2% as of January 2021 to 80% as of December 2021 [
      British Columbia Centre for Disease Control
      BCCDC COVID-19 surveillance dashboard.
      ]. We excluded from the analysis the individuals who reside in long-term care facilities because these individuals are very different from the general population with respect to their exposure risk and disease severity, given their comorbidity profile and characteristics. In addition, the transfer of these patients to hospitals was irregular over time and across local regions.

      2.3 Outcome and exposures

      The outcome of interest for the study was hospitalization or ICU admission with a positive SARS-CoV-2 test within 14 days before or up to 3 days after hospitalization. We excluded nosocomial cases flagged in notifiable disease reporting systems and SARS-CoV-2-positive cases with specimen collection >3 days after hospital admission [
      • Nasreen S
      • Febriani Y
      • Velásquez García HA
      • Zhang G
      • Tadrous M
      • Buchan SA
      • et al.
      Effectiveness of COVID-19 vaccines against hospitalization and death in Canada: a multiprovincial, test-negative design study.
      ].
      The following comorbidities and risk factors were assessed using medical visits, hospitalization, and/or prescription drugs: Alzheimer's disease/dementia, asthma, chronic heart disease: acute myocardial infarction, angina, heart failure, ischemic myocardial infarction, chronic obstructive pulmonary disease (COPD), cirrhosis, chronic kidney disease (CKD), depression, diabetes (categorized as no diabetes, non-insulin dependent, and insulin), epilepsy, gout, hypertension, stroke (ischemic, hemorrhagic, transitory ischemic attack), mood and anxiety disorders, osteoarthritis, osteoporosis, Parkinsonism, rheumatoid arthritis, substance use disorder, injection drug use (IDU), problematic alcohol use, cancer, immunosuppression, intellectual and developmental disabilities, and schizophrenia and psychotic disorders (SZP).
      Other factors taken into account for this analysis were age, vaccination status (categorized as not vaccinated or based on the timing of infection relative to receipt of dose as follows: partially vaccinated: ≥14 days after first dose or vaccinated: ≥14 days after second dose), and variant of concern (VOC; details about genomic sequence analysis can be found elsewhere) [
      • Fibke CD
      • Joffres Y
      • Tyson JR
      • Colijn C
      • Janjua NZ
      • Fjell C
      • et al.
      Spike mutation profiles associated with SARS-CoV-2 breakthrough infections in Delta emerging and predominant time periods in British Columbia.
      ]. Variable definitions and diagnostic codes used to identify comorbidities are presented in Appendix B of the Supplementary file.

      2.4 Statistical analysis

      We compared the demographic characteristics and comorbidities among the overall analytic sample, those requiring ambulatory care, and those requiring hospitalization (Table 1). We also summarized the distribution of characteristics among unvaccinated adult cases (Table 2) and among vaccinated adult cases (Table 3). Age was summarized in terms of median and interquartile range (IQR) and categorized for the analyses. Categorical variables were summarized as frequencies and percentages.
      Table 1Distribution of characteristics in confirmed (lab-tested) COVID-19 adult cases during 2021, British Columbia COVID-19 Cohort.
      AmbulatoryHospitalizedOverallP-value
      (N = 153,963)(N = 8546)(N = 162,509)
      SexFemale77,213 (50.2%)3,656 (42.8%)80,869 (49.8%)<0.001
      Male76,750 (49.8%)4,890 (57.2%)81,640 (50.2%)
      Age (years)Median (Q1-Q3)37 (27-50)60 (45-72)38 (28-52)<0.001
      Age group<20 Years5852 (3.8%)41 (0.5%)5,893 (3.6%)<0.001
      20-29 Years42,304 (27.5%)533 (6.2%)42,837 (26.4%)
      30-39 Years37,305 (24.2%)1003 (11.7%)38,308 (23.6%)
      40-49 Years27,722 (18.0%)1,114 (13.0%)28,836 (17.7%)
      50-59 Years21,223 (13.8%)1,534 (18.0%)22,757 (14.0%)
      60-69 Years12,939 (8.4%)1,739 (20.3%)14,678 (9.0%)
      70-79 Years4925 (3.2%)1,465 (17.1%)6,390 (3.9%)
      80+ Years1693 (1.1%)1,117 (13.1%)2,810 (1.7%)
      Health authorityFraser69,169 (44.9%)3,542 (41.4%)72,711 (44.7%)<0.001
      Interior25,138 (16.3%)1,703 (19.9%)26,841 (16.5%)
      Northern11,781 (7.7%)1,143 (13.4%)12,924 (8.0%)
      Vanc. Coastal34,369 (22.3%)1,546 (18.1%)35,915 (22.1%)
      Vanc. Island12,283 (8.0%)603 (7.1%)12,886 (7.9%)
      Unknown1,223 (0.8%)9 (0.1%)1232 (0.8%)
      Income (quintile,

      1 = low - 5 = high)
      1st28,991 (18.8%)2,579 (30.2%)31,570 (19.4%)<0.001
      2nd29,034 (18.9%)1,785 (20.9%)30,819 (19.0%)
      3rd28,296 (18.4%)1,503 (17.6%)29,799 (18.3%)
      4th28,433 (18.5%)1,285 (15.0%)29,718 (18.3%)
      5th25,721 (16.7%)1,021 (11.9%)26,742 (16.5%)
      Unknown13,488 (8.8%)373 (4.4%)13,861 (8.5%)
      Material deprivation index (quintile,

      1 = less deprived -

      5 = more deprived)
      1st25,338 (16.5%)983 (11.5%)26,321 (16.2%)<0.001
      2nd28,965 (18.8%)1,345 (15.7%)30,310 (18.7%)
      3rd27,316 (17.7%)1,583 (18.5%)28,899 (17.8%)
      4th27,585 (17.9%)1,805 (21.1%)29,390 (18.1%)
      5th25,605 (16.6%)25,605 (16.6%)27,494 (16.9%)
      Unknown19,154 (12.4%)941 (11.0%)20,095 (12.4%)
      Social deprivation index (quintile,

      1 = less deprived -

      5 = more deprived)
      1st31,012 (20.1%)1,552 (18.2%)32,564 (20.0%)<0.001
      2nd29,379 (19.1%)1,486 (17.4%)30,865 (19.0%)
      3rd23,983 (15.6%)1,306 (15.3%)25,289 (15.6%)
      4th23,595 (15.3%)1,345 (15.7%)24,940 (15.3%)
      5th26,840 (17.4%)1,916 (22.4%)28,756 (17.7%)
      Unknown19,154 (12.4%)941 (11.0%)20,095 (12.4%)
      Asthma20,521 (13.3%)1,568 (18.3%)22,089 (13.6%)<0.001
      Cirrhosis538 (0.3%)230 (2.7%)768 (0.5%)<0.001
      Cancer, lymphoma706 (0.5%)172 (2.0%)878 (0.5%)<0.001
      Cancer, solid15,917 (10.3%)1,799 (21.1%)17,716 (10.9%)<0.001
      Cancer, metastatic2,903 (1.9%)459 (5.4%)3362 (2.1%)<0.001
      Chronic kidney disease4,230 (2.7%)1605 (18.8%)5,835 (3.6%)<0.001
      Chronic obstructive pulmonary disease2,107 (1.4%)876 (10.3%)2983 (1.8%)<0.001
      DiabetesNo diabetes144,493 (93.8%)6412 (75.0%)150,905 (92.9%)<0.001
      Non-insulin dependent7,817 (5.1%)1,487 (17.4%)9,304 (5.7%)
      Insulin- dependent1,653 (1.1%)647 (7.6%)2,300 (1.4%)
      Obesity4,219 (2.7%)479 (5.6%)4698 (2.9%)<0.001
      Malnutrition2,283 (1.5%)427 (5.0%)2,710 (1.7%)<0.001
      Myocardial infarct (acute)1,124 (0.7%)399 (4.7%)1,523 (0.9%)<0.001
      Chronic heart disease (combined)5,538 (3.6%)1,630 (19.1%)7,168 (4.4%)<0.001
      Heart failure1,276 (0.8%)671 (7.9%)1,947 (1.2%)<0.001
      Hypertension17,415 (11.3%)3,430 (40.1%)20,845 (12.8%)<0.001
      Ischemic heart disease (combined)5,037 (3.3%)1,408 (16.5%)6,445 (4.0%)<0.001
      Problematic alcohol use8,276 (5.4%)1,200 (14.0%)9,476 (5.8%)<0.001
      Injection drug use8,328 (5.4%)1179 (13.8%)9,507 (5.9%)<0.001
      Immunosuppression3,513 (2.3%)561 (6.6%)4,074 (2.5%)<0.001
      Alzheimer/dementia234 (0.2%)155 (1.8%)389 (0.2%)<0.001
      Depression38,208 (24.8%)3,315 (38.8%)41,523 (25.6%)<0.001
      Intellectual & developmental disability895 (0.6%)106 (1.2%)1,001 (0.6%)<0.001
      Epilepsy1,186 (0.8%)160 (1.9%)1,346 (0.8%)<0.001
      Parkinsonism85 (0.1%)51 (0.6%)136 (0.1%)<0.001
      Rheumatoid arthritis1,466 (1.0%)273 (3.2%)1,739 (1.1%)<0.001
      Schizophrenia & psychotic disorders2,150 (1.4%)466 (5.5%)2,616 (1.6%)<0.001
      Variant of concernNon-variant of concern9,353 (6.1%)556 (6.5%)9,909 (6.1%)<0.001
      Alpha17,270 (11.2%)1003 (11.7%)18,273 (11.2%)
      Beta98 (0.1%)7 (0.1%)105 (0.1%)
      Gamma12,827 (8.3%)1,083 (12.7%)13,910 (8.6%)
      Delta38,540 (25.0%)3,180 (37.2%)41,720 (25.7%)
      Omicron6,958 (4.5%)100 (1.2%)7,058 (4.3%)
      Not sequenced68,917 (44.8%)2,617 (30.6%)71,534 (44.0%)
      Vaccination statusNot vaccinated90,252 (58.6%)6,508 (76.2%)96,760 (59.5%)<0.001
      Partially vaccinated16,063 (10.4%)1,136 (13.3%)17,199 (10.6%)
      Vaccinated47,648 (30.9%)902 (10.6%)48,550 (29.9%)
      Vanc. = Vancouver
      Table 2Distribution of characteristics in confirmed (lab-tested) COVID-19 unvaccinated adult cases during 2021, British Columbia COVID-19 Cohort.
      AmbulatoryHospitalizedOverallP-value
      (N = 90,252)(N = 6508)(N = 96,760)
      SexFemale43,140 (47.8%)2,797 (43.0%)45,937 (47.5%)<0.001
      Male47,112 (52.2%)3,711 (57.0%)50,823 (52.5%)
      Age (years)Median (Q1-Q3)36 (27-49)57 (43-70)37 (27-51)<0.001
      Age group<20 Years26,285 (29.1%)437 (6.7%)26,722 (27.6%)<0.001
      20-29 Years3,825 (4.2%)35 (0.5%)3,860 (4.0%)
      30-39 Years22,419 (24.8%)857 (13.2%)23,276 (24.1%)
      40-49 Years15,835 (17.5%)955 (14.7%)16,790 (17.4%)
      50-59 Years11,918 (13.2%)1,253 (19.3%)13,171 (13.6%)
      60-69 Years6889 (7.6%)1,338 (20.6%)8227 (8.5%)
      70-79 Years2,410 (2.7%)1,010 (15.5%)3420 (3.5%)
      80+ Years671 (0.7%)623 (9.6%)1,294 (1.3%)
      Health authorityFraser42,259 (46.8%)2,745 (42.2%)45,004 (46.5%)<0.001
      Interior15,074 (16.7%)1,310 (20.1%)16,384 (16.9%)
      Northern7,491 (8.3%)910 (14.0%)8,401 (8.7%)
      Vanc. Coastal19,603 (21.7%)1,118 (17.2%)20,721 (21.4%)
      Vanc. Island5,481 (6.1%)420 (6.5%)5,901 (6.1%)
      Unknown344 (0.4%)5 (0.1%)349 (0.4%)
      Income (quintile,

      1 = low - 5 = high)
      1st17,930 (19.9%)1,870 (28.7%)19,800 (20.5%)<0.001
      2nd17,924 (19.9%)1,370 (21.1%)19,294 (19.9%)
      3rd16,373 (18.1%)1,177 (18.1%)17,550 (18.1%)
      4th15,659 (17.4%)998 (15.3%)16,657 (17.2%)
      5th13,163 (14.6%)782 (12.0%)13,945 (14.4%)
      Unknown9,203 (10.2%)311 (4.8%)9,514 (9.8%)
      Material deprivation index (quintile,

      1 = less deprived -

      5 = more deprived)
      1st12,901 (14.3%)716 (11.0%)13,617 (14.1%)<0.001
      2nd15,363 (17.0%)1,027 (15.8%)16,390 (16.9%)
      3rd15,490 (17.2%)1,225 (18.8%)16,715 (17.3%)
      4th16,873 (18.7%)1,416 (21.8%)18,289 (18.9%)
      5th17,199 (19.1%)1,426 (21.9%)18,625 (19.2%)
      Unknown12,426 (13.8%)698 (10.7%)13,124 (13.6%)
      Social deprivation index (quintile,

      1 = less deprived -

      5 = more deprived)
      1st18,749 (20.8%)1,207 (18.5%)19,956 (20.6%)<0.001
      2nd16,844 (18.7%)1,132 (17.4%)17,976 (18.6%)
      3rd13,403 (14.9%)1,008 (15.5%)14,411 (14.9%)
      4th13,437 (14.9%)1,031 (15.8%)14,468 (15.0%)
      5th15,393 (17.1%)1,432 (22.0%)16,825 (17.4%)
      Unknown12,426 (13.8%)698 (10.7%)13,124 (13.6%)
      Asthma11,293 (12.5%)1,123 (17.3%)12,416 (12.8%)<0.001
      Cirrhosis299 (0.3%)144 (2.2%)443 (0.5%)<0.001
      Cancer, lymphoma339 (0.4%)97 (1.5%)436 (0.5%)<0.001
      Cancer, solid8525 (9.4%)1,214 (18.7%)9739 (10.1%)<0.001
      Cancer, metastatic1544 (1.7%)289 (4.4%)1833 (1.9%)<0.001
      Chronic kidney disease2,082 (2.3%)983 (15.1%)3065 (3.2%)<0.001
      Chronic obstructive pulmonary disease1,045 (1.2%)516 (7.9%)1,561 (1.6%)<0.001
      DiabetesNo diabetes85,162 (94.4%)5,087 (78.2%)90,249 (93.3%)<0.001
      Non-insulin dependent4,271 (4.7%)1,005 (15.4%)5276 (5.5%)
      Insulin dependent819 (0.9%)416 (6.4%)1235 (1.3%)
      Obesity2170 (2.4%)357 (5.5%)2,527 (2.6%)<0.001
      Malnutrition1,245 (1.4%)271 (4.2%)1,516 (1.6%)<0.001
      Myocardial infarct (acute)587 (0.7%)263 (4.0%)850 (0.9%)<0.001
      Chronic heart disease (combined)2,838 (3.1%)1,038 (15.9%)3,876 (4.0%)<0.001
      Heart failure635 (0.7%)383 (5.9%)1,018 (1.1%)<0.001
      Hypertension9,152 (10.1%)2,298 (35.3%)11,450 (11.8%)<0.001
      Ischemic heart disease (combined)2,588 (2.9%)903 (13.9%)3,491 (3.6%)<0.001
      Problematic alcohol use5,353 (5.9%)885 (13.6%)6,238 (6.4%)<0.001
      Injection drug use5,550 (6.1%)888 (13.6%)6,438 (6.7%)<0.001
      Immunosuppression1,925 (2.1%)344 (5.3%)2,269 (2.3%)<0.001
      Alzheimer/dementia115 (0.1%)78 (1.2%)193 (0.2%)<0.001
      Depression21,716 (24.1%)2,456 (37.7%)24,172 (25.0%)<0.001
      Intellectual & developmental disability576 (0.6%)83 (1.3%)659 (0.7%)<0.001
      Epilepsy701 (0.8%)109 (1.7%)810 (0.8%)<0.001
      Parkinsonism43 (0.0%)24 (0.4%)67 (0.1%)<0.001
      Rheumatoid arthritis779 (0.9%)174 (2.7%)953 (1.0%)<0.001
      Schizophrenia & psychotic disorders1,424 (1.6%)339 (5.2%)1763 (1.8%)<0.001
      Variant of concernNon-variant of concern8,432 (9.3%)474 (7.3%)8,906 (9.2%)<0.001
      Alpha14,393 (15.9%)789 (12.1%)15,182 (15.7%)
      Beta83 (0.1%)<5 (0.1%)87 (0.1%)
      Gamma10,243 (11.3%)792 (12.2%)11,035 (11.4%)
      DeltaDelta18,580 (20.6%)2,341 (36.0%)20,921 (21.6%)
      Omicron442 (0.5%)15 (0.2%)457 (0.5%)
      Not sequenced38,079 (42.2%)2,093 (32.2%)40,172 (41.5%)
      Vanc. = Vancouver
      Table 3Distribution of characteristics in confirmed (lab-tested) COVID-19 vaccinated
      14 days or more after second vaccine dose. Vanc. = Vancouver
      adult cases during 2021, British Columbia COVID-19 Cohort.
      AmbulatoryHospitalizedOverallP-value
      (N = 47,648)(N = 902)(N = 48,550)
      SexFemale25,757 (54.1%)368 (40.8%)26,125 (53.8%)<0.001
      Male21,891 (45.9%)534 (59.2%)22,425 (46.2%)
      Age (years)Median (Q1-Q3)39 (29-52)70 (56-80)39 (29-53)<0.001
      Age group<20 Years11,699 (24.6%)38 (4.2%)11,737 (24.2%)<0.001
      20-29 Years1,416 (3.0%)<5 (0.4%)1420 (2.9%)
      30-39 Years11,345 (23.8%)62 (6.9%)11,407 (23.5%)
      40-49 Years9,131 (19.2%)55 (6.1%)9,186 (18.9%)
      50-59 Years7,082 (14.9%)114 (12.6%)7,196 (14.8%)
      60-69 Years4,627 (9.7%)177 (19.6%)4,804 (9.9%)
      70-79 Years1,677 (3.5%)210 (23.3%)1,887 (3.9%)
      80+ Years671 (1.4%)242 (26.8%)913 (1.9%)
      Health authorityFraser20,076 (42.1%)333 (36.9%)20,409 (42.0%)<0.001
      Interior6,720 (14.1%)200 (22.2%)6,920 (14.3%)
      Northern2,941 (6.2%)116 (12.9%)3,057 (6.3%)
      Vanc. Coastal11,459 (24.0%)157 (17.4%)11,616 (23.9%)
      Vanc. Island5621 (11.8%)95 (10.5%)5,716 (11.8%)
      Unknown831 (1.7%)<5 (0.1%)832 (1.7%)
      Income (quintile,

      1 = low - 5 = high)
      1st7,664 (16.1%)312 (34.6%)7,976 (16.4%)<0.001
      2nd7,920 (16.6%)183 (20.3%)8,103 (16.7%)
      3rd9,048 (19.0%)129 (14.3%)9,177 (18.9%)
      4th9,923 (20.8%)140 (15.5%)10,063 (20.7%)
      5th10,137 (21.3%)112 (12.4%)10,249 (21.1%)
      Unknown2956 (6.2%)26 (2.9%)2,982 (6.1%)
      Material deprivation index (quintile,

      1 = less deprived -

      5 = more deprived)
      1st10,024 (21.0%)125 (13.9%)10,149 (20.9%)<0.001
      2nd10,663 (22.4%)143 (15.9%)10,806 (22.3%)
      3rd9,018 (18.9%)153 (17.0%)9,171 (18.9%)
      4th7,784 (16.3%)162 (18.0%)7,946 (16.4%)
      5th5451 (11.4%)192 (21.3%)5,643 (11.6%)
      Unknown4,708 (9.9%)127 (14.1%)4,835 (10.0%)
      Social deprivation index (quintile,

      1 = less deprived -

      5 = more deprived)
      1st9,127 (19.2%)138 (15.3%)9,265 (19.1%)<0.001
      2nd9,560 (20.1%)153 (17.0%)9,713 (20.0%)
      3rd7,990 (16.8%)130 (14.4%)8,120 (16.7%)
      4th7,676 (16.1%)132 (14.6%)7,808 (16.1%)
      5th8,587 (18.0%)222 (24.6%)8,809 (18.1%)
      Unknown4,708 (9.9%)127 (14.1%)4,835 (10.0%)
      Asthma6,879 (14.4%)205 (22.7%)7,084 (14.6%)<0.001
      Cirrhosis165 (0.3%)43 (4.8%)208 (0.4%)<0.001
      Cancer, lymphoma269 (0.6%)43 (4.8%)312 (0.6%)<0.001
      Cancer, solid5,523 (11.6%)303 (33.6%)5826 (12.0%)<0.001
      Cancer, metastatic1,011 (2.1%)100 (11.1%)1,111 (2.3%)<0.001
      Chronic kidney disease1,509 (3.2%)302 (33.5%)1,811 (3.7%)<0.001
      Chronic obstructive pulmonary disease770 (1.6%)191 (21.2%)961 (2.0%)<0.001
      Diabetes (treatment)No diabetes mellitus44,686 (93.8%)578 (64.1%)45,264 (93.2%)<0.001
      Non-insulin dependent2,388 (5.0%)205 (22.7%)2,593 (5.3%)
      Insulin dependent574 (1.2%)119 (13.2%)693 (1.4%)
      Obesity1555 (3.3%)61 (6.8%)1616 (3.3%)<0.001
      Malnutrition748 (1.6%)82 (9.1%)830 (1.7%)<0.001
      Myocardial infarct (acute)376 (0.8%)71 (7.9%)447 (0.9%)<0.001
      Chronic heart disease (combined)1900 (4.0%)295 (32.7%)2195 (4.5%)<0.001
      Heart failure441 (0.9%)161 (17.8%)602 (1.2%)<0.001
      Hypertension5,889 (12.4%)530 (58.8%)6,419 (13.2%)<0.001
      Ischemic heart disease (combined)1,722 (3.6%)246 (27.3%)1,968 (4.1%)<0.001
      Problematic alcohol use1,843 (3.9%)122 (13.5%)1,965 (4.0%)<0.001
      Injection drug use1,612 (3.4%)103 (11.4%)1,715 (3.5%)<0.001
      Immunosuppression1,174 (2.5%)108 (12.0%)1,282 (2.6%)<0.001
      Alzheimer/dementia68 (0.1%)42 (4.7%)110 (0.2%)<0.001
      Depression11,974 (25.1%)369 (40.9%)12,343 (25.4%)<0.001
      Intellectual & developmental disability202 (0.4%)12 (1.3%)214 (0.4%)<0.001
      Epilepsy354 (0.7%)23 (2.5%)377 (0.8%)<0.001
      Parkinsonism30 (0.1%)14 (1.6%)44 (0.1%)<0.001
      Rheumatoid arthritis474 (1.0%)53 (5.9%)527 (1.1%)<0.001
      Schizophrenia & psychotic disorders401 (0.8%)38 (4.2%)439 (0.9%)<0.001
      Variant of concern27 (0.1%)<5 (0%)27 (0.1%)NA
      Alpha72 (0.2%)2 (0.2%)74 (0.2%)
      Beta0 (0%)0 (0%)0 (0%)
      Gamma69 (0.1%)<5 (0.4%)73 (0.2%)
      Delta14,008 (29.4%)573 (63.5%)14,581 (30.0%)
      Omicron6442 (13.5%)82 (9.1%)6524 (13.4%)
      Not sequenced27,030 (56.7%)27,030 (56.7%)27,271 (56.2%)
      a 14 days or more after second vaccine dose.Vanc. = Vancouver
      We assessed the risk factors associated with hospital admission by estimating odds ratios (ORs) through multivariable logistic regression models and then stratified our analysis by vaccination status. These results are presented in Figure 1 and the tables for these models, as well as the analyses stratified by age groups, are presented in Tables S2-S10 of Appendix C of the Supplementary file. We also performed additional sensitivity analyses to examine the potential waning effect of vaccination by stratifying our analyses by time since full vaccination status. The results of these analyses are presented in Tables S11-S14 of Appendix C of the Supplementary file.
      Figure 1
      Figure 1Factors associated with hospitalization status in multivariable logistic regression analysis among confirmed COVID-19 adult cases during 2021, BC COVID-19 Cohort. *Odds ratios adjusted for the variables presented in the figure, as well as Health Authority, income (dissemination area level), and variant of concern. In addition, odds ratios for the “overall” are adjusted for vaccination status.

      3. Results

      3.1 Demographic characteristics

      The characteristics of the study population are presented in Table 1. Of the 162,509 cases included in the analysis, 153,963 (94.7%) were ambulatory cases and the remaining 8,546 (5.3%) were hospital admissions. Although the male sex represented only a slightly greater proportion of the overall confirmed COVID-19 cases (50.2%), it represented an even greater proportion (57.2%) of the hospitalized cases. The overall median age of COVID-19 cases was 38 years (IQR: 28-52); the median age of hospitalized cases was 60 years (IQR: 45-72). The highest proportion of ambulatory cases was in the 20-29 years age group (27.5%), but the highest proportion of cases requiring hospitalization admission was in the 60-69 years age group (20.3%).

      3.2 Risk factors

      We found a higher proportion of comorbidities among hospitalized cases than ambulatory cases; respectively, asthma (18.3% vs 13.3%), cirrhosis (2.7% vs 0.3%), COPD (10.3% vs 1.4%), obesity (5.6% vs 2.7%), myocardial infarction (4.7% vs 0.7%), chronic heart disease (19.1% vs 3.6%), heart failure (7.9% vs 0.8%), hypertension (40.1% vs 11.3%), ischemic heart disease (16.5% vs 3.3%), problematic alcohol use (14.0% vs 5.4%), immunosuppression (6.6% vs 2.3%), depression (38.8% vs 24.8%), intellectual and developmental disability (1.2% vs 0.6%), epilepsy (1.9% vs 0.8%), Parkinsonism (0.6% vs 0.1%), rheumatoid arthritis (3.2% vs 1.0%), and SZP (5.5% vs 1.4%). Also, there was a higher proportion of individuals with IDU among hospitalized cases than ambulatory cases (13.8% vs 5.4%). The Delta variant represented 25.0% of the ambulatory cases but a greater percentage of hospital admissions (37.2%). Although 58.6% of ambulatory cases were unvaccinated, an even greater proportion (76.2%) of the hospitalized cases were unvaccinated individuals. Vaccinated individuals represented only 10.6% of the hospitalized cases compared with 30.9% among the ambulatory cases (Table 1).
      In the adjusted logistic regression model (Table S2; Figure 1), age (P-trend <0.001 across age groups with increasing risk with older age [adjusted OR (aOR), age 30-39 years = 2.04; 95% CI: 1.83-2.27, to aOR age >80 years = 40.76; 95% CI: 35.50-46.79 compared with age 20-29 years), male sex (aOR = 1.31; 95% CI: 1.25-1.38), asthma (aOR = 1.12; 95% CI: 1.05-1.20), COPD (aOR = 1.61; 95% CI: 1.45, 1.78), cirrhosis (aOR = 2.55; 95% CI: 2.11-3.08), CKD (aOR = 1.95; 95% CI: 1.80-2.11), diabetes (non-insulin dependent), aOR = 1.31; 95% CI: 1.22-1.42, insulindependent aOR = 2.85; 95% CI: 2.54-3.20), hypertension (aOR = 1.19; 95% CI: 1.12-1.27), heart failure (aOR = 1.42; 95% CI: 1.26-1.60), IDU (aOR = 2.33; 95% CI: 2.13-2.56), problematic alcohol use (aOR = 1.54; 95% CI: 1.41-1.68), immunosuppression (aOR = 2.04; 95% CI: 1.83-2.29), Alzheimer disease/dementia (aOR = 1.40; 95% CI: 1.09-1.78), SZP (aOR = 1.90; 95% CI: 1.68-2.16), multiple sclerosis (aOR = 2.64; 95% CI: 1.77-3.96), Parkinsonism (aOR = 2.14, 95% CI: 1.43-3.19), rheumatoid arthritis (aOR = 1.29, 95% CI: 1.11-1.51), obesity (aOR = 1.73, 95% CI: 1.55-1.94), weight loss (aOR = 1.34, 95% CI: 1.18-1.52), intellectual and developmental disability (aOR = 2.05, 95% CI: 1.62-2.59), lymphoma (aOR = 1.61, 95% CI: 1.31-1.97), and metastatic cancer (aOR = 1.49, 95% CI: 1.32-1.69) were significantly associated with increased hospitalization.
      Also, compared with non-VOC lineage, the Delta (aOR = 3.22; 95% CI: 2.90-3.59), Alpha (aOR = 1.65, 95% CI: 1.46-1.86), Gamma (aOR = 3.09, 95% CI: 2.74-3.49), Omicron (aOR = 2.41; 95% CI: 1.90-3.07), and nonsequenced variants (aOR = 1.25; 95% CI: 1.12-1.39) were significantly associated with increased hospitalization. In addition, compared with no vaccination, full vaccination (aOR = 0.15; 95% CI: 0.14-0.17) and partial vaccination (aOR = 0.52; 95% CI: 0.49-0.57) were associated with reduced odds of hospitalization (Table S2).

      3.2.1 Risk factors by vaccination status

      The proportion of males in the unvaccinated group was higher than in the vaccinated group (52.5% vs 46.2%). The proportion of males who received ambulatory care was larger in the unvaccinated group than in the vaccinated group (52.2% vs 45.9%). Otherwise, the distribution of characteristics was similar across vaccination status (Table 2 and Table 3).
      For vaccinated individuals (Table S4 and Figure 1), an increased odds of hospitalization by increasing age was only observed for older age groups, 50-59 years (aOR = 2.95, 95% CI: 2.01-4.33), 60-69 years (aOR = 4.82, 95% CI: 3.29, 7.07), 70-79 years (aOR = 11.92, 95% CI: 8.02- 17.71), and ≥80 years (aOR = 24.25, 95% CI: 16.02, 36.71). However, for unvaccinated adult cases (Table S3 and Figure 1), there was a graded increase in the odds of hospitalization with age, starting at age group 30-39 years. In addition, the magnitude of association of each age was much stronger among unvaccinated individuals than among vaccinated individuals (Figure 1).
      Although the comorbidity risk factors for hospitalization were similar among vaccinated and unvaccinated individuals, the magnitude of association (aORs) for many of the risk factors were higher among vaccinated individuals than unvaccinated individuals: COPD (2.00 vs 1.41), cirrhosis (3.08 vs 2.39), IDU (3.17 vs 2.22), immunosuppression (3.03 vs 1.80), multiple sclerosis (7.39 vs 2.02), rheumatoid arthritis (2.20 vs 1.21), weight loss (1.87 vs 1.22), lymphoma (2.35 vs 1.38), and metastatic cancer (1.98 vs 1.43), respectively. CKD (aORs = 1.80 vs 1.93), obesity (1.37 vs 1.84), and SZP (1.58 vs 1.90) were the only conditions whose magnitude of association were higher among unvaccinated individuals than vaccinated individuals. Furthermore, asthma was a significant risk factor among unvaccinated individuals but not for vaccinated individuals (Table S3 and Table S4).

      3.2.2 Risk factors by age group

      The magnitude of association (aORs) for most of the comorbidities was highest for the youngest age group (18-49 years) than the two older age groups (50-69 years and ≥80 years): COPD (2.88 vs 1.80 vs 1.76), cirrhosis (3.73 vs 2.56 vs 1.71), CKD (2.48 vs 2.44 vs 1.84), non-insulin dependent diabetes (2.23 vs 1.38 vs 1.17), insulin-dependent diabetes (3.85 vs 3.17 vs 2.03), heart failure (2.11 vs 1.38 vs 1.55), hypertension (1.79 vs 1.33 vs 1.12), problematic alcohol use (1.62 vs 1.36 vs 1.52), immunosuppression (2.08 vs 1.88 vs 1.92), SZP (2.17 vs 1.51 vs 1.89), intellectual and developmental disability (1.48 vs 2.28 vs 0), lymphoma cancer (2.09 vs 1.46 vs 1.57), and metastatic cancer (1.67 vs 1.71 vs 1.30), respectively (Table S6, Table S8, and Table S10).
      Although being vaccinated was associated with reduced odds of hospitalization across the three stratified age groups, the benefit of being vaccinated appeared to be greatest among the 50-69 years age group (aOR = 0.13; 95% CI: 0.11, 0.15), followed by the 18-49 years age group (aOR = 0.15; 95% CI: 0.13, 0.18), and then ≥70 years age group (aOR = 0.20; 95% CI: 0.17, 0.23) (Table S6, Table S8, and Table S10).

      3.3 Sensitivity analyses

      The sensitivity analyses did not provide evidence to show that there was a difference by the analyzed vaccination strata, suggesting that there was no significant waning effect of vaccination (Tables S11-S14 of Appendix C of the Supplementary file).

      4. Discussion

      In this large population-based study, we assessed the risk factors for COVID-19 hospitalization after breakthrough infection among individuals who received vaccination and those who did not receive vaccination using data from 162,509 confirmed COVID-19 adult cases collected from January 1, 2021 to December 31, 2021 in the Canadian province of BC. In our analysis, we found many patient characteristics and comorbidities to be associated with hospitalization. However, the magnitude of association of these characteristics differed between vaccinated and unvaccinated individuals. Older age was the strongest risk factor for hospitalization overall and had a bigger relative impact in unvaccinated than in vaccinated individuals. Indeed, the odds of hospitalization only increased with increasing age from 50-59 years and older in vaccinated individuals, whereas there was a graded increase with increasing age in unvaccinated individuals. The association of various comorbidities was similar or, in some cases, slightly higher among vaccinated individuals for some comorbidities. We also found that compared with non-VOC lineage, the Delta, Alpha, Gamma, and Omicron variants were significantly associated with higher hospitalization risk, which was consistent with other studies [
      • Fisman DN
      • Tuite AR.
      Evaluation of the relative virulence of novel SARS-CoV-2 variants: a retrospective cohort study in Ontario, Canada.
      ,
      • Funk T
      • Pharris A
      • Spiteri G
      • Bundle N
      • Melidou A
      • Carr M
      • et al.
      Characteristics of SARS-CoV-2 variants of concern B.1.1.7, B.1.351 or P.1: data from seven EU/EEA countries, weeks 38/2020 to 10/2021.
      ,
      • Nyberg T
      • Twohig KA
      • Harris RJ
      • Seaman SR
      • Flannagan J
      • Allen H
      • et al.
      Risk of hospital admission for patients with SARS-CoV-2 variant B.1.1.7: cohort analysis.
      ,
      • Veneti L
      • Seppälä E
      • Larsdatter Storm M
      • Valcarcel Salamanca B
      • Alnes Buanes E
      • Aasand N
      • et al.
      Increased risk of hospitalisation and intensive care admission associated with reported cases of SARS-CoV-2 variants B.1.1.7 and B.1.351 in Norway, December 2020 -May 2021.
      ].
      We found age to be the strongest independent risk factor for hospitalization, which was consistent with findings from our previous study [
      • Velásquez García HA
      • Wilton J
      • Smolina K
      • Chong M
      • Rasali D
      • Otterstatter M
      • et al.
      Mental health and substance use associated with hospitalization among people with COVID-19: a population-based cohort study.
      ]. A recent rapid review also found age to be the most significant risk factor for severe outcomes, noting that adults aged >60 years may have a five-fold increase in hospitalization and mortality from COVID-19 compared with individuals aged <45 years [
      • Wingert A
      • Pillay J
      • Gates M
      • Guitard S
      • Rahman S
      • Beck A
      • et al.
      Risk factors for severity of COVID-19: a rapid review to inform vaccine prioritisation in Canada.
      ]. Our stratified analysis by vaccination status found that for vaccinated individuals, age as an independent risk factor was only significant for older age groups (>50 years). However, for unvaccinated adults, the increased odds of hospitalization were significant across all the age groups, with a graded increase in the odds of hospitalization with age. Furthermore, the magnitude of association was much higher among unvaccinated individuals than vaccinated individuals, similar to findings from Ontario Province in Canada [
      Public Health Ontario
      Severe Outcomes among Confirmed Cases of COVID-19 Following Vaccination in Ontario: December 14, 2020 to June 19, 2022.
      ]. This highlights the need for additional interventions among unvaccinated individuals to reduce the risk of severe disease, such as treatment with antiviral agents (e.g., nirmatrelvir/ritonavir). It also highlights the success of vaccination in reducing the increased risk of hospitalization associated with increasing age.
      In younger age groups (18-49 years age group), the magnitude of association was higher for many comorbidities than in older age groups. We also found that for most of the comorbidities that we assessed, the magnitude of association between these comorbidities and hospitalization was higher among vaccinated individuals than unvaccinated individuals. The risk of hospitalization present among vaccinated individuals with certain comorbidities, such as cancers, immunosuppression, and rheumatological diseases, have been noted in other studies [
      • Lang R
      • Humes E
      • Coburn SB
      • Horberg MA
      • Fathi LF
      • Watson E
      • et al.
      Analysis of severe illness after postvaccination COVID-19 breakthrough among adults with and without HIV in the US.
      ,
      • Wright BJ
      • Tideman S
      • Diaz GA
      • French T
      • Parsons GT
      • Robicsek A.
      Comparative vaccine effectiveness against severe COVID-19 over time in US hospital administrative data: a case-control study.
      ]. This may be the result of the underlying immune dysfunction in these conditions or could also be related to the fact that the vaccination roll-out was prioritized for older individuals and individuals with comorbidities [
      • Velásquez García HA
      • Wilton J
      • Smolina K
      • Chong M
      • Rasali D
      • Otterstatter M
      • et al.
      Mental health and substance use associated with hospitalization among people with COVID-19: a population-based cohort study.
      ,

      Government of British Columbia. COVID-19 immunization plan - Province of British Columbia 2021, https://web.archive.org/web/20210228021441/https://www2,gov.bc.ca/gov/content/covid-19/vaccine/plan; 2021 [accessed 07 July 2022].

      ].
      A major strength of our study is its large sample size, which enabled us to produce more precise estimates of effect sizes and also increased the representativeness of our findings. Our use of population-based cases rather than hospital or selected cases also reduced potential selection bias and ensured that our findings are generalizable to the general population. In addition, we objectively identified infection status using polymerase chain reaction and assessed VOC through whole genome sequencing. Furthermore, we ascertained vaccination status with the records from the Provincial Immunization Registry, which contains the records for all administered vaccines in BC. Likewise, we were able to assess a wide range of comorbidities and other risk factors using validated algorithms.
      Our findings should be interpreted in light of the following limitations. First, there is a possibility for misclassification of patient characteristics and morbidities because of the use of administrative data. Second, the COVID-19 assessment was based on BC testing guidelines, which not only varied over the pandemic period but could also differ from the guidelines of other jurisdictions, thereby limiting the generalizability of our findings to other contexts. Also, even though we considered many variables in our analyses, there is still a potential for unmeasured confounders, which could not be accounted for. In addition, this analysis is limited to those who sought health care/testing and thus may not be representative of the whole population of BC. Also, the testing rates may differ by vaccination status; however, this was not accounted for. Given that not many people had received booster doses at the time of our study, future studies should focus on disentangling the specific impact of booster doses on COVID-19-related outcomes.

      5. Conclusion

      To the best of our knowledge, this is one of the largest population-based studies examining the risk factors for hospitalization among patients with COVID-19 after vaccination. Given the higher risk of hospitalization among vaccinated older individuals and those with certain comorbidities, our findings also highlight the need for adding additional layers of protection from severe disease among those at higher risk, with improved access to antiviral treatments, such as nirmatrelvir/ritonavir, and the need for further vaccine booster doses.

      Declaration of competing interest

      N.Z.J. participated in advisory boards for AbbVie and has spoken for AbbVie and Gilead not related to the current work. The other authors have no competing interests to declare.

      Funding

      This work was supported by the BC Centre for Disease Control and the Canadian Institutes of Health Research (Grant # VR5-172683 and OV4-170361).

      Ethical approval

      This study was reviewed and approved by the Research Ethics Board of the University of BC (approval # H20-02097).

      Acknowledgments

      The BCC19C was established and is maintained through operational support from Data Analytics, Reporting, and Evaluation and BC Centre for Disease Control at the Provincial Health Services Authority. The authors acknowledge the assistance of the Provincial Health Services Authority, BC Ministry of Health, and the Regional Health Authority staff involved in data access, procurement, and management. The authors gratefully acknowledge the residents of BC whose data are integrated in the BCC19C.

      Author contributions

      Conceptualization: H.A.V.G. and N.Z.J.; writing-original draft preparation: P.A.A.; methods: H.A.V.G. and N.Z.J.; analysis: H.A.V.G. and P.A.A.; writing - review and editing: P.A.A., H.A.V.G., S.H., J.W., D.R., M.B., H.S., K.S., and N.Z.J.; supervision and project administration: N.Z.J.; funding acquisition: N.Z.J.; all authors have read and agreed to the published version of the manuscript.

      Data availability statement

      The study is based on data contained in various provincial registries and databases. Access to the data could be requested through the BC Centre for Disease Control Institutional Data Access for researchers who meet the criteria for access to confidential data. Requests for the data may be sent to [email protected].

      Disclaimer

      All inferences, opinions, and conclusions drawn in this manuscript are those of the authors and do not reflect the opinions or policies of the Data Steward(s).

      Appendix. Supplementary materials

      References

      1. Johns Hopkins University. COVID-19 Map, https://coronavirus.jhu.edu/map.html; 2022 [accessed 24 July 2022].

      2. British Columbia Centre for Disease Control. British Columbia COVID-19 Dashboard, https://experience.arcgis.com/experience/a6f23959a8b14bfa989e3cda29297ded; 2022a [accessed 24 July 2022].

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